Combined sequence and copy number analysis improves diagnosis of limb girdle and other myopathies

Figures

• 

  Figure 1. Age and ethnicity distributions of cases in the project. (A) Case number counts by decades. (B) Case number counts by ethnicity.

• 

  Figure 2. Summary of different limb girdle muscular dystrophy and other overlapping muscular dystrophy subtypes identified in “The Lantern Focused Neuromuscular Panel.” Molecular diagnosis was established in autosomal recessive subtypes with the identification of two pathogenic variants in the same gene or one pathogenic variant and one variant of uncertain significance in the same gene. Molecular diagnosis was established in autosomal dominant subtypes with the identification of one pathogenic variant.

• 

  Figure 3. Summary of oculopharyngeal muscular dystrophy (OPMD) cases. (A) Inheritance mechanisms of PABPN1 related OPMD. Expansion of a GCN trinucleotide repeat in exon 1 of the PABPN1 gene is associated with OPMD. It is inherited in either an autosomal dominant or an autosomal recessive manner. Normal alleles have 10 GCN repeats encoding 10 alanine amino acids. Autosomal dominant alleles have 12 to 17 GCN repeats and autosomal recessive alleles have 11 GCN repeats. Heterozygous 11‐GCN repeats have been observed in some individuals with mild adult‐onset OPMD. (B) Number of identified cases with different GCN trinucleotide repeat in exon 1 of the PABPN1 gene.

• 

  Figure 4. Ethnicity distribution of the DYSF pathogenic variants. (A) Dysferlinopathy cases in the project by ethnicity. (B) The c.2643+1G>A pathogenic variant in DYSF gene was identified in majority of African Americans. (C) The c.4253G>A (p.Gly1418Asp) pathogenic variant in DYSF gene was identified only in Hispanic individuals in this project. N/A, not available.

• 

  Figure 5. Copy number variant and sequence variants identified in the ANO5 gene. (A) Copy number loss of exon 1 to 22 and sequence variant c.191dup in exon 5 were detected in ANO5 of a 52‐year‐old male with proximal and distal muscle weakness, exercise intolerance, and muscle pain (ARMD44; Table 2). (B) Copy number loss of exons 14 to 22 and sequence variant c.2222C>A (p.Ser741Tyr) in exon 19 were detected in ANO5 of a 53‐year‐old male with proximal muscle weakness and LGMD (ARMD46; Table 2).

• 

  Figure 6. Copy number variant and sequence variants identified in CAPN3 and SGCG genes. (A) Intra genic copy number loss of exon 2 to 9 in CAPN3 and sequence variant c.2318_2321dup in exon 22 of CAPN3 was detected in an 18‐year‐old male with proximal muscle weakness and elevated creatine kinase (ARMD109; Table 2). (B) Copy number loss of entire SGCG gene and sequence variant c.702G>A (p.Met234Ile) in exon 7 of the SGCG gene in a 38‐year‐old male with hypotonia, and proximal and distal muscle weakness (ARMD462; Table 2).